This application addresses broad Challenge Area (03) Biomarker Discovery and Validation, and the specific Challenge Topic that this application addresses is: 03-DK-101 Discovery of biomarkers for disease risk, progression or response to therapy in diseases of interest to NIDDK. The Challenge: Despite tremendous progress in treatment, patients with type 1 diabetes continue to die 15 years earlier, experience excess morbidity and have medical costs over 10 times higher than the general population. The risk of coronary artery disease and diabetic nephropathy is still greatly increased and responsible for 80% of deaths in these patients. Diabetic nephropathy and coronary artery disease are intertwined, suggesting common pathways, and yet current risk prediction is inadequate. Study Rationale: Nearly 25% of T1D patients develop end-stage renal disease. The conventional theory is that the sequence of events leading to diabetic nephropathy begins from microalbuminuria, progressing to overt proteinuria and eventual end-stage renal disease. Primary prevention with ACE/ARB treatment usually begins when persistent microalbuminuria is found. However, recent prospective studies using serial measurements of kidney function estimated from serum cystatin C have changed this paradigm by demonstrating that decline in glomerular filtration may begin in the absence of microalbuminuria or continue despite remission of microalbuminuria. By their mid 40's, over 70% of men and 50% of women with type 1 diabetes develop coronary artery calcification (CAC) - a marker of significant atherosclerotic plaque burden. Cardiovascular disease is particularly prevalent among patients with renal disease, but most cardiac events occur in patients with normal albumin excretion rates. Evidence has accumulated that diabetic nephropathy and CAC are parallel, rather than sequential, complications of type 1 diabetes, sharing a number of important predictors. Accurate prediction of the individual's global cardio-renal risk is needed to guide treatment choices. As a result, there is a recognized need for better risk partitioning, either from the discovery of additional biomarkers or the application of superior methods for discrimination of disease states. Our Approach: We are proposing to use the biobank of 652 adults with type 1 diabetes who have been thoroughly genotyped and prospectively followed for development of diabetic nephropathy and coronary artery disease by the Coronary Artery Calcification in Type 1 Diabetes study (CACTI, R01 HL61753, 1999- 2009) to develop and validate integrated biomarker prediction models for cardio-renal complications in type 1 diabetes. Our study aims are the investigation of biomarkers within the well-characterized CACTI cohort for 1) early progressive renal function decline, 2) the presence and progression of coronary artery calcium, and the 3) development of combined renal and cardiovascular disease burden. Renal disease and coronary artery disease (CAD) are the leading causes of death among adults with type 1 diabetes, but traditional screening tests (urinary albumin and serum creatinine) for renal disease are inadequate, and traditional CAD risk factors (dyslipidemia, hypertension, smoking, obesity) do not fully explain the increased burden of disease associated with type 1 diabetes. Renal and cardiovascular complications are intertwined, suggesting shared pathways. Increased systemic inflammation is present in type 1 diabetes and inflammatory mediators such as uric acid, vitamin D and bone metabolism markers have been suggested to play a role in both renal and cardiovascular diseases. As a result, it is of critical public health importance to discover and validate new biomarkers for cardio-renal disease among adults with type 1 diabetes. PUBLIC HEALTH RELEVANCE: Renal disease and coronary artery disease (CAD) are the leading causes of death among adults with type 1 diabetes, but traditional screening tests (urinary albumin and serum creatinine) for renal disease are inadequate, and traditional CAD risk factors (dyslipidemia, hypertension, smoking, obesity) do not fully explain the increased burden of disease associated with type 1 diabetes. Renal and cardiovascular complications are intertwined, suggesting shared pathways. Increased systemic inflammation is present in type 1 diabetes and inflammatory mediators such as uric acid, vitamin D and bone metabolism markers have been suggested to play a role in both renal and cardiovascular diseases. As a result, it is of critical public health importance to discover and validate new biomarkers for cardio-renal disease among adults with type 1 diabetes.